rs121918416

Positions:

• chr5-151851440-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000171.4(GLRA1):​c.862G>A​(p.Val288Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:2 U:1
• Conservation: PhyloP100: 7.73

Genes affected

GLRA1 (HGNC:4326): (glycine receptor alpha 1) The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a transmembrane_region Helical; Name=2 (size 20) in uniprot entity GLRA1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000171.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.862G>A	p.Val288Met	missense_variant	7/9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.862G>A	p.Val288Met	missense_variant	7/9		NP_001139512.1
GLRA1	NM_001292000.2	c.613G>A	p.Val205Met	missense_variant	6/8		NP_001278929.1
GLRA1	XM_047417105.1	c.910G>A	p.Val304Met	missense_variant	7/9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.862G>A	p.Val288Met	missense_variant	7/9	1	NM_000171.4	ENSP00000274576	P4
GLRA1	ENST00000455880.2	c.862G>A	p.Val288Met	missense_variant	7/9	1		ENSP00000411593	A1
GLRA1	ENST00000471351.2	n.1145G>A		non_coding_transcript_exon_variant	7/8	1
GLRA1	ENST00000462581.6	c.*620G>A		3_prime_UTR_variant, NMD_transcript_variant	6/8	1		ENSP00000430595

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperekplexia 1 Pathogenic:2

Pathogenic, no assertion criteria provided	curation	GeneReviews	Oct 04, 2012	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2001	- -

GLRA1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2024

The GLRA1 c.862G>A variant is predicted to result in the amino acid substitution p.Val288Met. This variant has been reported in an individual with hyperekplexia; the variant was inherited from the individual's father, though the only phenotype noted in the father was an exaggerated startle response (del Giudice et al. 2001. PubMed ID: 11781706). This variant has not been reported in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.4	N;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.79		Gain of disorder (P = 0.0426);Gain of disorder (P = 0.0426);
MVP		0.88
MPC		2.1
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.88
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918416; hg19: chr5-151231001;